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Biomedical subjects

W G Forssmann

Publications and source records attributed to W G Forssmann.

At least 91 records · Page 5Linked to original sources
PubMed1997

Natriuresis after cardiopulmonary bypass: relationship to urodilatin, atrial natriuretic factor, antidiuretic hormone, and aldosterone.

OBJECTIVE: Recent studies suggest that urodilatin from the kidneys rather than atrial natriuretic factor from the heart is the more important member of the family of natriuretic peptides involved in the normal regulation of renal sodium and water excretion. We thus examined the relationship between natriuresis, urodilatin, and atrial natriuretic factor in patients after cardiopulmonary bypass, a procedure known to increase levels of atrial natriuretic factor significantly. METHODS: Excretion rates of sodium and water were correlated with the excretion of urodilatin and with circulating levels of atrial natriuretic factor, antidiuretic hormone, aldosterone, and plasma renin activity during a period of 16 hours in 12 patients having had coronary artery bypass operations and with approximately a 400% elevation in levels of atrial natriuretic factor. RESULTS: Natriuresis did not correlate with atrial natriuretic factor, antidiuretic hormone, aldosterone, or plasma renin activity. Excretion rates of urodilatin, however, correlated significantly with excretion rates of sodium (r = 0.74, p = 0.03), urine flow (r = 0.83, p = 0.01), and with levels of serum sodium (r = 0.82, p = 0.01). CONCLUSION: These results suggest an important role for urodilatin, greater than that of atrial natriuretic factor, in the regulation of renal excretion of sodium and water after cardiopulmonary bypass surgery.

Adult↗
PubMed1997

Effects of sodium nitroprusside in the rat cortical collecting duct are independent of the NO pathway.

Recently we described K+ channels in the basolateral membrane of principal cells of rat cortical collecting duct (CCD) which are regulated by a cGMP-dependent protein kinase (Pflugers Arch 429:338-344, 1995). We examined the effects of the NO-liberator sodium nitroprusside (SNP) on single channel activity and membrane voltage (Vm) in principal cells of rat CCD, and on transepithelial voltage, lumen-to-bath Na+ fluxes, and osmotic water permeability in isolated perfused rat CCD tubules. While in patch clamp experiments SNP (10 microM) hyperpolarized principal cells from -54 +/- 10 mV to -71 +/- 5 mV (N = 5) and increased the activity of the described K+ channels from 0.05 +/- 0.03 to 0.45 +/- 0.14 (N = 5) in cell-attached and from 0.04 +/- 0.02 to 0.25 +/- 0.05 (N = 4) in excised patch clamp experiments, it had no effect on basal or AVP-dependent transepithelial voltage, Na+ fluxes, or the osmotic water permeability. In addition, neither 50 microM SIN-1, another liberator of NO, nor 1 mM L-NAME, an inhibitor of the NO-synthase, changed Vm significantly. Furthermore, in cGMP-assays SNP failed to increase intracellular cGMP in CCD segments. Thus, we conclude that in the rat CCD transport is not regulated via the NO-pathway and that SNP acts as an cGMP independent activator of K+ channels in the basolateral membrane of these cells.

Animals↗
PubMed1997

Synthesis, biological activity and isomerism of guanylate cyclase C-activating peptides guanylin and uroguanylin.

Recently, the peptides guanylin and uroguanylin were identified as endogenous ligands of the membrane-bound guanylate cyclase C (GC-C) that is mainly expressed in the intestinal epithelium. In the present study, bioactive guanylin and uroguanylin have been prepared by solid-phase methodology using Fmoc/HBTU chemistry. The two disulfide bonds with relative 1/3 and 2/4 connectivity have been introduced selectively by air oxidation of thiol groups and iodine treatment of Cys(Acm) residues. Using this strategy, several sequential derivatives were prepared. Temperature-dependent HPLC characterization of the bioactive products revealed that guanylin-related peptides exist as a mixture of two compounds. The isoforms are interconverted within approximately 90 min, which prevents their separate characterization. This effect was not detected for uroguanylin-like peptides. Synthetic peptides were tested for their potential to activate GC-C in cultured human colon carcinoma cells (T84), known to express high levels of GC-C. The results obtained show that both disulfide bonds are necessary for GC-C activation. The presence of the amino-terminally neighboring residues of Cys104 for guanylin and Cys100 for uroguanylin has been found to be essential for GC-C stimulation. Unexpectedly, a hybrid peptide obtained from substitution of the central tripeptide AYA of guanylin by the tripeptide VNV of uroguanylin was not bioactive.

Amino Acid Sequence↗
PubMed1997

Urodilatin (INN:ularitide) as a new drug for the therapy of acute renal failure following cardiac surgery.

1. Acute renal failure is a severe complication following major cardiac surgery. 2. The effects of urodilatin were evaluated in a randomized, double-blind trial in patients suffering from incipient acute renal failure following cardiac surgery. 3. In the urodilatin group (n = 7) acute renal failure was reverted, whereas in the placebo group (n = 7) six patients had to be haemofiltered or haemodialysed (P < 0.005). 4. Urodilatin induced a rapid onset of diuresis in contrast to placebo-treated patients, who remained oliguric. 5. In the placebo group four of seven patients died while still on haemodialysis (mortality rate 57.1%) during a postoperative follow-up period of 60 days, while all patients treated with urodilatin survived. 6. On the basis of these results it would appear that urodilatin is an effective drug for the treatment of incipient oliguric acute renal failure following cardiac surgery and for avoiding haemodialysis/haemofiltration.

Acute Kidney Injury↗
PubMed1997

ANP protects against reoxygenation-induced hypercontracture in adult cardiomyocytes.

It was investigated whether atrial natriuretic peptide (ANP) or the related peptide urodilatin can be used for protecting cardiomyocytes against reoxygenation-induced hypercontracture. Isolated ventricular cardiomyocytes (from adult rats) were used as the experimental model. When the cells were submitted to substrate-free anoxia (135 min) and subsequent reoxygenation (30 min), the onset of reoxygenation provoked their hypercontracture. It was studied whether the temporary presence of ANP or urodilatin (1 nM to 1 microM) or 8-bromo-guanosine 3',5'-cyclic monophosphate (8-BrcGMP; 1 microM to 1 mM) during the last 15 min of anoxia and the first 15 min of reoxygenation prevented hypercontracture. It was found that ANP (1 microM) prevented hypercontracture in 82 +/- 8% (SD), urodilatin (1 microM) in 80 +/- 9%, and 8-BrcGMP (1 mM) in 72 +/- 10% of the cells (n = 40 cells). When ANP (1 microM) was added during the last 15 min of anoxia and the first 15 min of reoxygenation, the cellular concentration of cGMP increased from 0.41 +/- 0.04 to 2.80 +/- 0.81 pmol/mg protein (n = 6 cultures). The results show that the reoxygenation-induced hypercontracture in cardiomyocytes can be attenuated by the temporary presence of the stimulators of particulate guanylate cyclase, ANP or urodilatin.

Aerobiosis↗
PubMed1997

Prophylactic use of low-dose urodilatin for prevention of renal impairment following liver transplantation: a randomized placebo-controlled study.

Many therapeutic measures have been employed to prevent or at least ameliorate postoperative renal impairment following liver transplantation. Recent clinical phase II studies have demonstrated that the new natriuretic peptide urodilatin has beneficial effects on renal function following heart and liver transplantation. The present study reports the first prospective randomized placebo-controlled trial of prophylactic urodilatin administration following liver transplantation. Seventy consecutive recipients of primary liver transplants were included in the study following randomization, and 33 patients continuously received urodilatin at a dose of 20 ng/kg/min for 7 d. The remaining 37 patients received a placebo infusion for the same time period. The course of serum creatinine and urea did not differ between the two groups nor did the daily urine production. However, the urodilatin group showed a higher preoperative median serum creatinine and a significant reduction on days 1 and 2, whereas this observation was not made in the placebo group. Furthermore, less furosemide was administered to the patients in the urodilatin group during the first 2 d. The incidence of postoperative hemodialysis and the number of treatments did not differ between the groups either (urodilatin group 4, vs. placebo group 6 and 22 for both groups, respectively). Side effects of the urodilatin therapy were not detected. The prophylactic low-dose urodilatin administration resulted in a trend towards amelioration of the renal function, but did not result in significant differences between the two experimental groups. Further studies, using higher doses, will be required to define the value of urodilatin for prevention of renal impairment after liver transplantation.

Adolescent↗
PubMed1996

Pituitary adenylate cyclase-activating polypeptide: a potent activator of human intestinal ion transport.

To investigate the effects of PACAP-27 on electrolyte transport across the isolated human intestinal mucosa, changes in short-circuit current (Isc) were measured in Ussing chamber experiments. Serosally added PACAP-27 increased Isc in a concentration-dependent manner, eliciting a similar maximal effect in both the jejunal and the colonic mucosa. Bumetanide inhibited Isc responses, indicating stimulation of Cl- secretion. The potency and efficacy of PACAP-27 were comparable to those of VIP, suggesting that both peptides activate intestinal secretion by way of a common receptor located in the basolateral membrane of the intestinal epithelium.

Colon↗
PubMed1996

hDIP--a potential transcriptional regulator related to murine TSC-22 and Drosophila shortsighted (shs)--is expressed in a large number of human tissues.

We have cloned a 420 bp cDNA from a human fetal brain cDNA library in lambda encoding the human homologue of a DSIP-immunoreactive leucine zipper protein (DIP) isolated from porcine brain. The derived human protein (hDIP) shares a significant sequence identity with parts of the murine TSC-22 and Drosophila shs, both proteins which are discussed as functioning as transcriptional regulators. A similar role of hDIP is partially confirmed by the results of an RT-PCR analysis, demonstrating the widespread distribution of the protein among different human tissues.

Amino Acid Sequence↗
PubMed1996

Structural and functional characterization of vitronectin-derived RGD-containing peptides from human hemofiltrate.

Bioactive peptides derived from the adhesive plasma protein vitronectin are present at submicromolar concentrations in human hemofiltrate of patients with renal diseases and were isolated by a combination of high-efficiency chromatographic steps. The structural and functional properties of these peptides were characterized. Sequencing and mass spectrometry revealed the existence of peptide isoforms (5-6 kDa) which corresponded to the N-terminus (residues 1 to 44-50) of vitronectin. The isolated peptides bound directly to plasminogen-activator inhibitor-1 (PAI-1) and were effective competitors of the interaction of PAI-1 with isolated intact vitronectin or extracellular matrix. These functional properties were indistinguishable from the binding properties of a recombinant fusion protein containing residues 1-52 of vitronectin linked to a portion of glutathione S-transferase, expressed in Escherichia coli. Peptides containing the RGD sequence of vitronectin competed for vitronectin binding to the alpha v beta 3 integrin. No indication for direct growth-factor binding was noted, whereas natural peptides were found associated with PAI-1 as the major binding protein in plasma. These data demonstrate that functionally active vitronectin-derived peptides are released by unknown protease(s) from the mature protein and that these peptides are identical, in terms of activity, to recombinant vitronectin fragments. These natural peptides may interact with active PAI-1 in plasma or at extravascular sites and thereby interfere with established biological functions of intact vitronectin.

Amino Acid Sequence↗
PubMed1996

Specific determination of tyrosine-phosphorylated proteins and peptides by differential iodination.

A new method for the selective and quantitative determination of phosphotyrosine residues is presented using a differential iodination technique. Characterization of tyrosine-phosphorylated proteins was performed in a biological system using human U937 myeloid leukemia cells. The method is based on the saturation of free iodine binding sites using non-radioactive iodine. Samples are then treated with alkaline phosphatase. New iodine binding sites in dephosphorylated tyrosines are subsequently radio-iodinated, resulting in specific labeling of tyrosine phosphates. Separation is performed by RP-HPLC or sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Radiolabeled proteins are then identified using a radioactivity detector or autoradiography.

Alkaline Phosphatase↗
PubMed1996

Functional analysis of the human guanylin gene promoter.

Guanylin (GCAP-I, guanylate cyclase activating peptide I) and uroguanylin (GCAP-II, guanylate cyclase activating peptide II) are regulatory peptides involved in the regulation of the intestinal chloride / water balance. They share significant structural homology to the E. coli enterotoxin STa, which binds to the particulate guanylyl cyclase C causing diarrhea in mammals. In this study we report the functional analysis of the guanylin / GCAP-I gene promoter region. By means of the luciferase reporter gene assay, we demonstrate a strong promoter activity in T84 cells. Especially the first 160 bp of the 5'-flanking region of the gene seem to be essential for gene induction. Our findings are the basis for further identification of important regulatory elements of the corresponding gene.

Base Sequence↗
PubMed1996

Secretion of a urodilatin-like immunoreactive (URO-like-IR) substance from a human kidney cell line (HEK-293).

The aim of this study was to explore whether sodium chloride is involved in the release of urodilatin from epithelial human embryonic kidney cells (HEK-293). Using a highly specific urodilatin radioimmunoassay combined with HPLC, gel chromatography, and a cyclic GMP generating bioassay, we demonstrate that HEK-293 cells release a biologically active 3.5 kD, urodilatin-like immunoreactive substance. To show the effect of sodium on urodilatin release, HEK-293 cells were incubated with cell culture buffer containing 120, 130, 140, and 150 mmol/l sodium, respectively. Urodilatin secretion from HEK-293 cells is increased to 176% when extracellular sodium is raised to 150 mmol/l (control: 120 mmol/l = 100%). There was no significant difference when exposing the cells to 140 mmol/l or 150 mmol/l sodium. It is suggested, that beside the known extrarenal factors influencing urodilatin secretion, high cephalic sodium and cardiac volume load, urodilatin secretion might also be regulated by an intrarenal sodium sensitive mechanism.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Urodilatin secretion in salt-loaded Wistar rats.

The aim of our study was to investigate whether urodilation (URO, INN: ularitide) is present in rat urine and if URO excretion in the rat is influenced by dietary sodium intake. Therefore, three groups of Wistar rats were placed in metabolic cages where they received different sodium diets for 9 days (0.05%, 0.4%, and 8.0% NaCl, respectively). Food and water intake were determined by weight. At days -4, 2, 5, and 8 blood pressure was measured non invasively using the tail cuff method. After nine days rats were anesthetized and blood was drawn for serum electrolyte, plasma A-type natriuretic peptide (CDD/ANP-99-126), and plasma aldosterone concentration measurements. Using a highly specific antibody against URO combined with high performance liquid chromatography and gel chromatography, we were able to show that a URO-like substance of approx. 3.5 kD that is distinct from CDD/ANP-99-126, brain natriuretic peptide, and C-type natriuretic peptide, is present in rat urine. Sodium chloride loaded rats showed significantly increased urinary excretion rates of URO (p < 0.001), chloride (p < 0.001), sodium (p < 0.001), and the fractional excretion of sodium (p < 0.001). In the plasma, sodium (p < 0.01) and chloride (p < 0.001) increased, while potassium, hematocrit, osmolality, plasma CDD/ANP-99-126, as well as glomerular filtration rate (GFR), and systolic blood pressure did not change. Since CDD/ANP-99-126 is believed to be a natriuretic peptide, it is suggested that CDD/ANP-99-126 might participate in the natriuresis due to high dietary sodium intake. In sodium-loaded rats, however, plasma CDD/ANP-99-126 remains unchanged, while URO excretion increases with sodium excretion, independent of GFR and blood pressure. We conclude that URO secretion is stimulated by dietary salt loading and might be involved in the regulation of water and electrolyte metabolism in the rat.

Aldosterone↗
PubMed1996

Association between different psychotic disorders and the DRD4 polymorphism, but no differences in the main ligand binding region of the DRD4 receptor protein compared to controls.

The dopamine D4 receptor gene (DRD4 gene) is one of the important candidate genes for schizophrenia and other psychoses. In humans, several alleles with variable repeat numbers of a 48-base-pair element within the third exon are known. The corresponding receptor proteins differ in their pharmacological properties. It might be possible that specific alleles or genotypes predispose for schizophrenia and other psychoses. The aim of the present study was to investigate and compare the frequency of the DRD4 alleles and genotypes in healthy controls and patients suffering from schizophrenia, schizoaffective or affective disorders. The DRD4 subtypes of 92 controls, 91 patients with schizophrenia, 90 patients with affective and 20 with schizoaffective disorders were identified by a combination of Southern blot technique and PCR. Statistical analysis revealed several significant differences between controls and patients, e.g. an increased frequency of the D4.7 allele among patients with schizophrenia, schizoaffective or unipolar affective disorder. The results indicate a possible role of the DRD4 gene polymorphism in the pathophysiology of psychotic diseases. When a part of the DRD4 gene sequence containing the codons for the most important amino acids for dopamine binding in 9 controls, 9 patients with schizophrenia and 10 with affective disorders were compared, no differences could be found.

Adult↗
PubMed1996

Systematic isolation of circulating human peptides: the concept of peptide trapping.

The structural determination of circulating human peptides is essential to determine their correct posttranslationally processed form. Human hemofiltrate from patients with end stage renal disease is accessible in large quantities and is used as a source for the preparation of circulating peptides. After complete peptide extraction from hemofiltrate, a systematic separation with different chromatographic techniques is achieved. Single peptides are selected according to their mass and chromatographic elution position. Following chromatographic purification, amino acid sequence analysis is performed in combination with data base search. The identification of circulating peptides leads to numerous fragments resulting from cleavage of larger plasma proteins as well as to the discovery of new peptide hormones. The results obtained so far give insight into the degradation of plasma proteins such as fibrinogen, which results in the generation of fragments with biological activity themselves and in the identification of a novel cytokine HCC-1, the first member of beta-defensins in humans, hBD-1, and different peptides not present in any data base.

Amino Acid Sequence↗
PubMed1996

Acute renal failure following cardiac surgery is reverted by administration of Urodilatin (INN: Ularitide).

Acute renal failure (ARF) is a serious complication following cardiac surgery. This first controlled study was undertaken to verify, if Urodilatin (URO) infusion can revert incipient oliguric ARF after cardiac surgery. We conducted a randomized, double blind trial comparing 7 URO (20 ng/kg/min) with 7 placebo patients. Inclusion criterion was oliguria/anuria (< 0.5 ml/kg/hour) refractory to conventional treatment including administration of dopamine and furosemide. No patient in the URO treated group, but 6 patients in the placebo group had to be hemofiltered or hemodialyzed (p < 0.005) during the 7 day treatment period. In the URO group all 7 patients demonstrated a rapid recovery of diuresis after 2 - 8 hours of treatment that persisted throughout the treatment period. In contrast, placebo treated patients remained oliguric. Serum creatinine (SC) decreased in URO treated patients. No adverse effects were observed during URO administration. After termination of URO, 2 patients underwent hemodialysis for elevated blood urea nitrogen (BUN) values. In the postoperative follow-up period of 60 days, 4 out of 7 placebo treated patients died while still on hemodialysis. In contrast, all URO patients survived. URO is an effective drug to reverse oliguric ARF following cardiac surgery. Prolonged renal failure and renal replacement therapy can be avoided.

Acute Kidney Injury↗
PubMed1996

HCC-1, a novel chemokine from human plasma.

A novel CC chemokine, HCC-1, was isolated from the hemofiltrate of patients with chronic renal failure. HCC-1 has a relative molecular mass of 8,673 and consists of 74 amino acids including four cysteines linked to disulfide bonds. HCC-1 cDNA was cloned from human bone marrow and shown to code for the mature protein plus a putative 19-residue leader sequence. Mature HCC-1 has sequence identity of 46% with macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta, and 29-37% with the other human CC chemokines. Unlike MIP-1 alpha and the other CC chemokines, HCC-1 is expressed constitutively in several normal tissues (spleen, liver, skeletal and heart muscle, gut, and bone marrow), and is present at high concentrations (1-80 nM) in plasma. HCC-1 has weak activities on human monocytes and acts via receptors that also recognize MIP-1 alpha. It induced intracellular Ca2+ changes and enzyme release, but no chemotaxis, at concentrations of 100-1,000 nM, and was inactive on T lymphocytes, neutrophils, and eosinophil leukocytes. In addition, HCC-1 enhanced the proliferation of CD34+ myeloid progenitor cells. It was as effective as MIP-1 alpha, but about 100-fold less potent.

Amino Acid Sequence↗